Obesity is a public health problem globally, and two-thirds of US men are overweight or obese. For prostate cancer patients, the obesity epidemic is of concern since men who are overweight before or at the time of diagnosis are at increased risk of biochemical recurrence and cancer-specific mortality. There are several outstanding questions underlying the association between obesity and lethal prostate cancer whose answers are needed to shed light on the translational potential among prostate cancer patients. Our study aims to elucidate mechanisms underlying the link between obesity and lethal prostate cancer and identify patient subgroups more susceptible to the obesity milieu. We hypothesize that obesity may act through local tumor effects which are We hypothesize that obesity may act through local tumor effects which are the seed to increase a prostate cancer's lethal potential as well as via systemic effects that fuel the soil for metastatic growrth. We focus on metabolism and inflammation pathways - two domains with established links to obesity?and investigate biomarkers iri locally in prostate tissue as well as in circulation. Moreover, we employ a discovery-based aim in tumors to identify novel pathways enriched in the tumors of prostate cancer patients who are overweight and develop lethal cancer, and endeavor that may unveil new opportunities for secondary prevention. Our population-based study of obesity and lethal prostate cancer is nested among men with incident prostate cancer who were participants within the DF/HCG SPORE in Prostate Gancer biorepository for whom prostate tissue and blood specimens are available, and uniquely focuses on lethal cancer as the primary endpoint. Obesity represents a means to discover drivers of lethal prostate cancer, as well as being a modifiable risk factor in secondary prevention. Weight loss is challenging, and thus identifying specific pathways in tumors and in circulation most strongly underlying the obesity-lethal prostate cancer link is critical to inform on optimal prevention strategies. The translational goals ofthe project are the identification of patients at high risk of the consequences of obesity in order to inform the design of randomized trials and augment the success of secondary prevention strategies. The work will lead to a detailed understanding of the effect of prostatic and systemic drivers of obesity on lethal prostate cancer, an endeavor that will strengthen causality of the association.